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Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila
Open accessAbstract
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.
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“These findings have recently been called into question, however, with the report that the lifespan extension originally observed in the worm and fly studies was mostly due to confounding genetic background differences and not to the overexpression of sir-2.1 or dSir2, respectively (Burnett et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Burnett et al., 2011
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“recent reports fail to show robust effects of SIRT on lifespan in these same model systems (56).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [56]
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Metadata
- Authors
- Burnett, C., Valentini, S., Cabreiro, F., Goss, M., Somogyvári, M., Piper, M. D., Hoddinott, M., Sutphin, G. L., Leko, V., McElwee, J. J., Vazquez-Manrique, R. P., Orfila, A.-M., Ackerman, D., Au, C., Vinti, G., Riesen, M., Howard, K., Neri, C., Bedalov, A., Kaeberlein, M., Sőti, C., Partridge, L., & Gems, D.
- Affiliations
- University College London (GB)
- Semmelweis University (HU)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Inserm (FR)
- MRC Laboratory for Molecular Cell Biology (GB)
- Max Planck Institute for Biology of Ageing (DE)
- Corresponding author
- Gems, David
- ORCID
- Venue
- Nature
- Published
- 2011-09
- Volume
- 477
- Issue
- 7365
- Pages
- 482-485
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3188402
- OpenAlex
- W2074974899
- Cited by
- 624
- References
- 36
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 16 · 2023: 15 · 2022: 19 · 2021: 23 · 2020: 18 · 2019: 33 · 2018: 26 · 2017: 43 · 2016: 54 · 2015: 71 · 2014: 60 · 2013: 98 · 2012: 100
- FWCI
- 32.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust (081394)
- European Commission
- National Institutes of Health
- National Institute on Aging (R01AG031108, T32AG000057)
- National Cancer Institute (CA129132, R01CA129132)
- National Center for Research Resources
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- Sir2, sirtuins, lifespan extension, aging, dietary restriction, Caenorhabditis elegans, Drosophila melanogaster, outcrossing, sensory neurons, NAD+-dependent deacetylase
- MeSH terms
- Aging, Animals, Crosses, Genetic, Drosophila melanogaster, Female, Histone Deacetylases, Longevity, Male, RNA, Messenger, Gene Expression, Caenorhabditis elegans, Drosophila Proteins, Caenorhabditis elegans Proteins, Animals, Genetically Modified, Caloric Restriction, Sirtuins
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